US5391751A - 2,2-dimethylchromene derivatives, process for their preparation and pharmaceutical compositions in which they are present - Google Patents

2,2-dimethylchromene derivatives, process for their preparation and pharmaceutical compositions in which they are present Download PDF

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US5391751A
US5391751A US07/746,974 US74697491A US5391751A US 5391751 A US5391751 A US 5391751A US 74697491 A US74697491 A US 74697491A US 5391751 A US5391751 A US 5391751A
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product
dimethylchromene
derivatives
composition
mixture
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US07/746,974
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English (en)
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Georges Garcia
Alain Di Malta
Patrick Gautier
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RED BALLOON INVESTMENT Ltd
Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention relates to chromene derivatives having an antihypertensive and antiarrythmic activity. It also relates to a process for their preparation and pharmaceutical compositions in which they are present.
  • Belgian Patent 829 611 mentions a whole series of chroman-3-ol derivatives having an antihypertensive activity; these derivatives are characterized by the presence of a group NR 1 R 2 in the 4-position, in which is hydrogen or an optionally substituted hydrocarbon group and R 2 is hydrogen or an alkyl, it being possible for NR 1 R 2 to be a heterocyclic group containing from 3 to 8 atoms, which is unsubstituted or substituted by one or two methyl groups, and by the presence, in some cases, of a large number of possible substituents in the 6-position or 7-position.
  • European patent application published under number 76 075 describes chroman-3-ol derivatives having an antihypertensive activity which are characterized by the presence of a 2-oxopyrrolidin-1-yl group or a 2-oxopiperidino group in the 4-position and by the presence, in some cases, of numerous possible substituents, including the cyano group, in the 6-position or 7-position.
  • European patent application 93535 describes 2,2-dimethylchromene derivatives which are characterized by the presence of a 2-oxopiperidino or 2-oxopyrrolidin-1-yl group in the 4-position and by the presence, in some cases, of numerous possible substituents in the 6-position or 7-position.
  • 2,2-dimethylchromene derivatives which are characterized by the presence of a 2-oxo-1,2-dihydropyrid-1-yl group in the 4-position possess an excellent antihypertensive and antiarrhythmic activity and a very low toxicity.
  • the antihypertensive activity of the derivatives according to the present invention is greater than that of the corresponding chroman-3-ol derivatives.
  • the present invention relates to 2,2-dimethylchromene derivatives of the formula ##STR2## in which Z represents a halogen atom or a cyano, nitro, acetyl, phosphono or dialkoxyphosphoryl group, the alkoxy group containing 1 to 3 carbon atoms, and to the pharmaceutically acceptable salts of the phosphono group.
  • the pharmaceutically acceptable salts are preferably those of alkali metals and alkaline earth metals, such as the sodium and potassium salts, or these of organic bases such as triethanolamine, trometamol, ethanolamine, N-methylpiperidine or tert-butylamine.
  • the preferred halogen atoms are chlorine and bromine.
  • the present invention further relates to a process for the preparation of the compounds (I).
  • the said process comprises dehydrating the chroman-3-ol of the formula ##STR3## in which Z' represents a halogen atom or a cyano, nitro, acetyl or dialkoxyphosphoryl group, and, if desired, converting the dialkoxyphosphoryl group into the phosphono group, and then, if desired, converting the resulting phosphonic acid into its pharmaceutically acceptable salts.
  • Z' represents a halogen atom or a cyano, nitro, acetyl or dialkoxyphosphoryl group
  • Z' represents a halogen atom or a cyano, nitro, acetyl or dialkoxyphosphoryl group
  • Z' represents a dialkoxyphosphoryl group
  • this can be converted into the corresponding group by transesterification with a trimethylsilyl halide, preferably the bromide, and hydrolysis di(trimethylsilyl ester) simply by reaction with water.
  • a trimethylsilyl halide preferably the bromide
  • hydrolysis di(trimethylsilyl ester) simply by reaction with water.
  • Z represents a phosphono group and the said compound can be converts into one Of its pharmaceutically acceptable salts, for example those of alkali metals or alkaline earth metals, such as the sodium or potassium salts, or those of organic bases such as triethanolamine, trometamol, ethanolamine, tert-butylamine or N-methylpiperidine.
  • Dehydration of the chroman-3-ol is effected with an alkali metal hydride such as sodium hydride, in an inert solvent such as tetrahydrofuran, at a temperature of between 50° C. and 100° C.
  • an alkali metal hydride such as sodium hydride
  • an inert solvent such as tetrahydrofuran
  • the reaction for opening the epoxide III is carried out at a temperature of between 10° and 100° C. in an inert organic solvent such as dioxane, tetrahydrofuran, methyl tert-butyl ether, dimethyl sulfoxide or dimethylformamide, in tile presence of a basic condensation agent such as sodium hydride or a quaternary ammonium hydroxide like benzyltrimethylammonium hydroxide. Under these operating conditions, opening of the epoxide III leads to a chroman-3-ol derivative in the trans configuration.
  • an inert organic solvent such as dioxane, tetrahydrofuran, methyl tert-butyl ether, dimethyl sulfoxide or dimethylformamide
  • the starting epoxides of formula III are known or prepared by known methods.
  • the epoxide III in which Z' represents the cyano group is described in Belgian patent 852 955; tile epoxides III in which Z' represents the nitro group or an acetyl group are described in J. Med. Chem., 1983, 26, 1582-1589; the epoxides III in which Z' represents a halogen are prepared according to Tetrahedron, 1981, 37, (15), 2613-2616.
  • the starting epoxides of formula III in which Z' represents a dialkoxyphosphoryl group are not described in the literature. They can be prepared from 6-bromo-2,2-dimethylchromene (J. Chem. Soc., 1960, 3094-3098) of the formula ##STR5## by reaction with a trialkyl phosphite in the presence of nickel chloride at 180° C. and by reaction of the resulting compound of the formula ##STR6## in which Alk represents an alkyl containing from 1 to 3 carbon atoms, with N-bromosuccinimide in aqueous dimethyl sulfoxide.
  • the resulting bromohydrin of the formula ##STR7## in which Alk is as defined above, is then treated with an alkaline agent in a water/organic solvent mixture, for example water/dioxane, preferably at room temperature for a period of 8 to 20 hours, and the resulting epoxide of formula II in which Z' is a dialkoxyphosphoryl group is isolated by the conventional methods, for example by concentration of the reaction mixture and recovery of the residue with a solvent which removes the impurities, such as methylene chloride, washing with water and concentration.
  • a water/organic solvent mixture for example water/dioxane
  • the compounds of formula I increase the polarization of the smooth muscle fibers and have a vasodilative effect on the portal vein; their antihypertensive effect has been observed in animals.
  • the compounds according to the invention accelerate the repolarization of myocardial cells; their antiarrhythmic effect has been observed in parallel on an animal model.
  • the compounds according to the invention can be used in the treatment of hypertension and pathological disorders associated with contractions of the smooth muscle fibers of the gastrointestinal, respiratory, uterine and urinary systems, for example ulcers, asthma, premature uterine contraction and incontinence, and in the treatment of other cardiovascular pathological disorders such as angor, cardiac insufficiency and cerebral and peripheral vascular diseases. Furthermore, the compounds according to the invention can be used in the treatment of cardiac arrhythmia. Finally, the compounds of the present invention can be used for the topical treatment of alopecia.
  • the present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the invention, with suitable excipients.
  • suitable excipients are chosen according to the desired pharmaceutical form and the desired mode of administration.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, percutaneous or rectal administration
  • the active principles of formula I above, or their salts if appropriate can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit forms of administration include oral forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, sublingual and buccal forms, subcutaneous, intramuscular or intravenous forms and rectal forms.
  • the compositions according to the invention can be used in creams, ointments or lotions.
  • the daily dose of active principle can vary between 0.01 and 5 mg per kg of body weight.
  • Each unit dose can contain from 0.5 to 200 mg, preferably from 1 to 50 mg, of active ingredients combined with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 1000 mg, preferably 5 to 250 mg.
  • the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose or other appropriate substances or they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active principle continuously.
  • a preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active principle together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, an agent for imparting taste and an appropriate colorant.
  • a sweetener which is preferably calorie-free, methylparaben and propylparaben as antiseptics, an agent for imparting taste and an appropriate colorant.
  • Water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
  • suppositories are used which are prepared with binders melting at rectal temperature, for example cacao butter or polyethylene glycols.
  • aqueous suspensions, isotonic saline solutions or injectable sterile solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
  • the active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.
  • compositions of the present invention can contain, in addition to the products of formula I above or one of their pharmaceutically acceptable salts, other active principles such as, for example, tranquilizers or other drugs which can be useful in the treatment of the disorders or diseases indicated above.
  • a mixture containing 1.7 g of the product obtained in step A and 150 mg of sodium hydride in 50 ml of tetrahydrofuran is refluxed for 2 hours.
  • the tetrahydrofuran is evaporated off under vacuum, the residue is taken up with iced water and extraction is then carried out with ethyl acetate.
  • the organic phase dried over sodium sulfate and then evaporated under vacuum.
  • the residue is taken up in an isopropyl ether/ ethyl ether mixture (50/50, v/v). After filtration, washing with isopropyl ether and drying at 100° C. under vacuum, 800 mg of the expected product are collected.
  • the NMR spectrum is run at 250 MHz on a solution in DMSO.
  • a solution containing 6 g of 6-bromo-2,2-dimethylchromene, 20 ml of DMSO and 5 ml of water is prepared.
  • 5 g of N-bromosuccinimide are added in small portions at a temperature below 10° C. and the mixture is stirred for 1 hour.
  • 100 ml of water are added, extraction is then carried out twice with methylene chloride and the organic phase is washed with water, dried over sodium sulfate and concentrated to give 5.4 g of 3,6-dibromo-2,2-dimethyl-4-hydroxychromane.
  • the previous compound is dissolved in 200 ml of dioxane. 20 ml of a 10% solution of sodium hydroxide are added and the mixture is stirred for 12 hours at room temperature. The dioxane is concentrated, the residue is then taken up with 100 ml of methylene chloride and the organic phase is washed twice with water, dried over sodium sulfate and concentrated. The oil obtained is chromatographed on a silica column using a hexane/ethyl acetate mixture (98/2) as the eluent. This gives 2.2 g of the expected epoxide.
  • the compound obtained in the previous step is dissolved in 20 ml of THF, 1.5 g of 2-hydroxypyridine and 0.2 ml of benzyltrimethylammonium hydroxide are added and the mixture is then refluxed for 24 hours. It is dried over sodium sulfate and concentrated. The product crystallizes from isopropyl ether to give 1.5 g of the expected product.
  • a mixture containing 500 mg of the product obtained in the previous step, 20 ml of tetrahydrofuran and 40 mg of sodium hydride is refluxed for 3 hours.
  • the solvent is driven off, the residue is then taken up in ethyl ether and washed with water and the ether phase is then dried over sodium sulfate. It is left to crystallize in a refrigerator for 48 hours and the crystals are filtered off and washed with cyclohexane.
  • a mixture containing 2.1 g of 6-acetyl-2,2-dimethyl-3,4-epoxychromane and 1.7 g of 2-hydroxypyridine in 40 ml of tetrahydrofuran is refluxed for 16 hours in the presence of 0.4 ml of benzyltrimethylammonium hydroxide.
  • the mixture is cooled and the crystals formed are filtered off and washed with tetrahydrofuran. After drying under vacuum at 60° C., 1.5 g of the expected product are obtained.
  • compositions containing a product according to the invention were prepared.
  • Tablets can be prepared by wet granulation. Ethyl alcohol and purified water are used as auxiliary production solvents. After evaporation of these solvents, magnesium stearate is introduced in an external phase as a lubricant. The tablets are then coated.
  • product B described in European patent application 95535 and hereafter referred to as "product B".
  • the vein is subjected to a tension of 500 mg. After a period of stabilization (about 1 h 30 min), the spontaneous contractile activities are recorded with the aid of an isometric sensor. Each measurement is performed successively on 4 preparations.
  • the product is studied at successive increasing concentrations (15 min per concentration) until the spontaneous contractions have been totally inhibited.
  • the results are expressed in the form of the molar concentrations which causes a 50 per cent inhibition of the spontaneous contractile activities (IC 50 ).
  • the results column shows the IC 50 of the spontaneous contractile activities of isolated rat portal vein.
  • each chromene derivative according to the invention is at least 10 times greater than that of the corresponding chroman-3-ol derivative, while the comparison products A and B have similar activities.
  • the ventricular action potential is measured by the conventional microelectrode method.
  • the characteristic parameters were measured on the action potentials (AP) before and after the introduction of the test product at 3 successive increasing concentrations (30 minutes of perfusion per concentration). The concentration which produces a 50 per cent reduction in the duration of the AP is indicated (IC 50 ).
  • the Table shows that the duration of the action potential is markedly decreased.
  • concentration of SR 44866 which produces a 50 per cent reduction in this parameter is 10 times lower than that of product A, demonstrating a greater electrophysiologically activity on the membrane permeability responsible for this repolarization phase.
  • the electrophysiological profile of the compound studied shows that it has no significant effect on the rest potential and the maximum depolarization rate; this means that the compound studied has no local anesthetic activity.
  • the experiment is performed on male SHR (of the Wistar strain) aged between 11 and 12 weeks; under pentobarbital anesthesia, a catheter is implanted in a carotid artery on the day before the experiment.
  • the diastolic pressure (DP) and systolic pressure (SP) of the vigilant animals are recorded continuously 1 hour before and up to 2 hours after administration of the product.
  • the heart rate (HR) is determined from the pulse pressure and recorded continuously for the same time.
  • the products were administered orally in a volume of 2 ml per 100 g of body weight after suspension in a 5% aqueous solution of gum arabic.
  • the products according to the invention are powerful antihypertensives with an activity of the same order as or greater than that of product A.
  • the method used is the one described by Dupuis et al. (Br. J. Pharmacol., 1976, 58, p. 409), in which an acute infarction is caused by the insertion of a copper spiral into the coronary circulation, with the thorax closed off.
  • the ECG is measured by telemetry and the extrasystoles are analyzed and counted automatically While the animal is being monitored by an internal television circuit.
  • the products were administered orally to animals presenting at least 50 per cent of extrasystoles.
  • a compound representative of the present invention--SR 44866--administered orally at doses of 0.03 mg/kg and 0.1 mg/kg shows a substantial antiarrhythmic activity by reducing the number of extrasystoles or by restoring a sinus rhythm for a period varying from 45 minutes to 2 hours according to the animals.
  • the acute toxicity of a product representative of the invention--SR 44866-- was measured on a group of 10 mice by oral administration at different doses and compared with that of product A.
  • the lethal doses (LD) were calculated for the 2 products and are reported in Table 4 below.
  • the 2 products have a comparable toxicity whereas the activity of SR 44866 is about 10 times greater in the majority of the tests.
  • the products according to the invention have a greater therapeutic index than the reference product.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
US07/746,974 1987-10-12 1991-08-19 2,2-dimethylchromene derivatives, process for their preparation and pharmaceutical compositions in which they are present Expired - Fee Related US5391751A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US07/746,974 US5391751A (en) 1987-10-12 1991-08-19 2,2-dimethylchromene derivatives, process for their preparation and pharmaceutical compositions in which they are present

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR8714067A FR2621587B1 (fr) 1987-10-12 1987-10-12 Derives du dimethyl-2,2 chromene, procede pour leur preparation et composition pharmaceutiques les contenant
FR8714067 1987-10-12
US25560588A 1988-10-11 1988-10-11
US07/746,974 US5391751A (en) 1987-10-12 1991-08-19 2,2-dimethylchromene derivatives, process for their preparation and pharmaceutical compositions in which they are present

Related Parent Applications (1)

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US25560588A Continuation 1987-10-12 1988-10-11

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US (1) US5391751A (de)
EP (2) EP0556872A1 (de)
JP (1) JPH02180A (de)
KR (1) KR890006625A (de)
AR (1) AR246521A1 (de)
AT (1) ATE100095T1 (de)
AU (1) AU619766B2 (de)
CA (1) CA1329603C (de)
DE (1) DE3887068D1 (de)
DK (1) DK567188A (de)
FI (1) FI90545C (de)
FR (1) FR2621587B1 (de)
IE (1) IE940342L (de)
IL (1) IL88002A (de)
NO (1) NO171851C (de)
NZ (1) NZ226516A (de)
PT (1) PT88718B (de)
ZA (1) ZA887607B (de)

Cited By (1)

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DE3726261A1 (de) * 1986-12-23 1988-07-07 Merck Patent Gmbh Chromanderivate
US5284838A (en) * 1987-06-23 1994-02-08 Elf Sanofi Use of 2,2-dimethylchroman-3-ol derivatives in the treatment of asthma
JPH03500542A (ja) * 1988-05-09 1991-02-07 ビーチャム　グループ　ピーエルシー 新規な化合物及び治療法
EP0346724A1 (de) * 1988-06-16 1989-12-20 MERCK PATENT GmbH Chromanderivate
DE68921972T2 (de) * 1988-12-13 1995-11-16 Beecham Group Plc Benzopyran und verwandte Verbindungen.
DE3923839A1 (de) * 1989-07-19 1991-01-31 Beiersdorf Ag Benzopyran-derivate, verfahren zu ihrer herstellung und ihre verwendung sowie die verbindungen enthaltende zubereitungen
DE3924417A1 (de) * 1989-07-24 1991-01-31 Merck Patent Gmbh Chromanderivate
FR2654103B1 (fr) * 1989-11-06 1992-02-21 Sanofi Sa Derives d'amidino-4 chromanne, procede d'obtention et compositions pharmaceutiques les contenant.
FR2657872B2 (fr) * 1989-11-06 1992-06-12 Sanofi Sa Derive d'amidino-4 chromanne, procede d'obtention et compositions pharmaceutiques le contenant.
US5185345A (en) * 1989-11-06 1993-02-09 Sanofi 4-amidino pyrano (3,2-c) pyridine derivatives, and pharmaceutical compositions containing them
US5177616A (en) * 1991-12-02 1993-01-05 Matsushita Avionics Systems Stowable video display assembly
DE102004005179B4 (de) * 2004-02-02 2006-07-13 Wobben, Aloys, Dipl.-Ing. Windenergieanlage

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EP0346724A1 (de) * 1988-06-16 1989-12-20 MERCK PATENT GmbH Chromanderivate
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US6153627A (en) * 1986-12-23 2000-11-28 Merck Patent Gesellschaft Mit Beschrankter Haftung Chroman derivatives

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IE940342L (en) 1989-04-12
AR246521A1 (es) 1994-08-31
FI90545C (fi) 1994-02-25
CA1329603C (en) 1994-05-17
NO884533L (no) 1989-04-13
EP0556872A1 (de) 1993-08-25
DK567188D0 (da) 1988-10-11
ATE100095T1 (de) 1994-01-15
AU619766B2 (en) 1992-02-06
JPH02180A (ja) 1990-01-05
AU2366088A (en) 1989-04-13
ZA887607B (en) 1989-06-28
FR2621587B1 (fr) 1990-02-09
NO171851C (no) 1993-05-12
EP0312432A1 (de) 1989-04-19
IL88002A0 (en) 1989-06-30
IL88002A (en) 1994-08-26
DE3887068D1 (de) 1994-02-24
KR890006625A (ko) 1989-06-14
EP0312432B1 (de) 1994-01-12
FI884660A0 (fi) 1988-10-11
PT88718B (pt) 1992-12-31
DK567188A (da) 1989-04-13
FI884660A (fi) 1989-04-13
NZ226516A (en) 1990-05-28
FR2621587A1 (fr) 1989-04-14
NO884533D0 (no) 1988-10-11
NO171851B (no) 1993-02-01
FI90545B (fi) 1993-11-15

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